Clinical Research at the National Amyloidosis Centre

General background and terminology

Clinical studies

The aim of all clinical studies is to increase medical knowledge by
performing research in human volunteer participants. There are two types of clinical studies:

Observational studies

Clinical trials

Observational
studies

Observational studies involve structured assessment and follow up
evaluation of health outcomes in a group of patients over time. The investigators performing an observational
study do not assign the patients to a particular treatment or intervention, as
occurs in a clinical trial. Observational studies add to our understanding of the natural history of
a disease and give us information about how patients are treated and how they
respond to treatments. For example, the AL Chemotherapy (Alchemy) study at the NAC has gathered ‘real world’
data on all UK patients diagnosed with AL amyloidosis at the NAC, including the
treatment regimes they have received, the side effects experienced and the
patient outcomes.

Clinical
trials

Clinical trials involve evaluation of the effects of specific
interventions on human participants. Often
new drugs or interventions are compared to dummy drugs known as placebos. Sometimes a new drug is compared to an
existing drug. Researchers follow all
participants carefully to assess the effects of the trial drug. Drug development is a highly regulated and ordered process, consisting
of a series of clinical trial steps called phases. Each phase is designed to address a different
research question, and all new drugs are required to proceed through all the
phases in an orderly fashion.

Phase 1 trials:Initial safety trials on a new drug in humans. The aim of phase 1 trials is to evaluate
common side effects, to look at how the human body metabolises the drug and to establish
a tolerated dosage range. Participants
are often healthy volunteers.

Phase 2 trials:Phase 2 trials usually involve a small number of patients
with the condition being studied. These
trials evaluate drug safety in these patients and gather preliminary data on effectiveness.

Phase 3 trials:Phase 3 trials are conducted after the drug has been demonstrated as
effective in small numbers of patients with the condition studied. These trials usually involve a large number of
patients with the condition. These
trials provide more data on the effectiveness and safety of the drug in
patients with the condition being studied. If the
data from phase 3 trials are sufficient, then researchers may use it to apply
to the licensing authorities for marketing approval.

Phase 4 trials:Phase 4 trials are post-marketing trials carried out
after a drug has received regulatory approval. These trials gather additional information
about the safety and effectiveness of the drug.

Some other terms used in clinical studies

Randomised controlled trialThis means that a number of similar people are randomly
assigned to two or more groups. One
group (the experimental group) receives the drug being tested. The other (the control group) receives either
a dummy treatment (placebo), an alternative treatment or no treatment. Researchers follow both groups to compare the
outcomes in the experimental group and the control group.

PlaceboA dummy or sham treatment, received by the patients in the control group
of a controlled clinical trial.

Double
blindThis means that neither the patients nor the researchers know who is
receiving the study drug and who is receiving placebo. Drug and placebo materials are coded by an
independent third party who holds the code secretly until the study is
completed or a significant adverse effect requires ‘unblinding.’

Open labelThis means that both the patients and the researchers know what drug and
what dose is being administered.

MulticentreThis means that the trial includes patients and researchers in a number
of different sites, often from all around the world.

Informed consentThis is the procedure whereby the researchers explain all the important
information about the study to the patient. They ensure that the patient understands the
risks and benefits and that enrolment is voluntary. The patient then signs an informed consent
form.

Prospective studiesIn prospective studies, a group of people is recruited and then followed
over a period of time, in order to gather data regarding a specific study
question. For example the ALchemy study, discussed in more detail below, is a
prospective observational study. Patients with a diagnosis of systemic AL amyloidosis requiring
chemotherapy treatment are recruited at the NAC at the time of diagnosis. Routine clinical data are then collected over
time to give information on treatment, treatment toxicity and outcomes in these
patients.

In prospective drug trials, patients are recruited and then followed
over a period of time while they receive a study drug. Sometimes patients receiving the study drug
are compared to similar patients receiving an older, established drug, or to
patients receiving a placebo. Patient
data collected over time provides information that can be analysed to assess
the effect of the study drug.

Examples of ongoing prospective studies at the NAC include:

The REVEAL
study – a randomised phase 2 prospective trial of bortezomib combination
chemotherapy in patients with advanced stage disease. Patients are randomly assigned to receive
either bortezomib-dexamethasone or cyclophosphamide. Patient data is then collected over time, to
compare the outcomes with the two treatment regimes.

The
ALN-TTRSC in ATTR cardiac amyloidosis is an open label phase 2 prospective
trial. Patients with ATTR cardiac
amyloidosis will receive a series of injections of a drug that is in relatively
early stages of development, called ALN-TTRSC. They will then be followed to assess the safety and tolerability of the
drug.

ISIS TTR
Rx. The purpose of the trial is to
determine whether ISIS TTR Rx can slow or stop the nerve damage caused by ATTR
deposits in patients with familial amyloid polyneuropathy (FAP). This study will enrol late Stage 1 and early
Stage 2 FAP patients. Patients will receive
either ISIS TTR Rx or placebo for 65 weeks. This is a randomised controlled double blind phase 3 trial.

Retrospective studiesIn retrospective studies, data that have already been collected through
medical records or in a clinical study are analysed in order to address a new
question that the original study was not designed to address. For example, in a recent publication
co-authored by the NAC consultants and by European colleagues, treatment
outcomes in patients with advanced cardiac AL amyloidosis were evaluated
retrospectively. Data on these patients
were extracted from patient records and analysed. The results provided new information on
outcomes in this particular patient group, which had not previously been
assessed as distinct from the overall outcomes in all AL amyloidosis patients.

At present there are no on-going retrospective studies at the NAC.

Terms used in AL amyloidosis trials

Response to chemotherapy treatment for AL amyloidosis may be assessed by
the following criteria:

Trials taking place at the NAC

Trials for AL amyloidosis

ALchemy

The ALchemy (AL amyloidosis chemotherapy) study is a large, on-going, ‘real
world’ study of chemotherapy in systemic AL amyloidosis, funded by a grant from
the charity Myeloma UK. The NAC started this study in 2009 in order to address several
unanswered questions relating to patients with AL amyloidosis.

An unmet
needPrior to ALchemy, there had been no large systematic studies following
and monitoring patients with systemic AL amyloidosis from the time of diagnosis
(prospective studies). Studies that had
been carried out were small and usually did not include patients with severe
disease. Many patients were lost to
follow up after their initial visits to the NAC. It was therefore hard to assess accurately
exactly which chemotherapy treatments patients around the country were
receiving, what side effects they experienced and how the disease and treatment
impacted on their quality of life. ALchemy aimed to fill these gaps in our knowledge and to help us to
improve our clinical practice accordingly. Our goal was to gain a ‘real world’ picture of the disease by close
monitoring of all patients with systemic AL amyloidosis regardless of age or
disease severity.

Who is
eligible for ALchemy?All patients diagnosed with systemic AL amyloidosis in need of treatment
are eligible for enrolment in ALchemy if they are able and willing to give
informed consent and have had no (or minimal) prior therapy.

ALchemy
monitoringPatients enrolled in the study are monitored closely by NAC clinical
research nurses. Before ALchemy
started, our standard follow up protocol involved an NAC assessment at
diagnosis then every 6 months.

The ALchemy
protocol involves:

Evaluation of patients' response to treatment after 3 months, after just 3 cycles of treatment.

Requesting that the patients' local treating physicians and nurses supply us with data
regarding chemotherapy and other treatments and side effects after every cycle
(every month). We provide a form
for the data.

Requesting that patients send us blood samples after every cycle (every month) so we can
check free light chain (FLC) concentrations and serum protein electrophoresis
(SPE). We provide the blood sample tubes
and pre-addressed padded envelopes and patients can go to their GP or local
hospital clinic to have the blood drawn.

We wanted to assess the feasibility of this intensive, early monitoring
approach. We also wanted to evaluate
whether such early assessments could lead to better treatment outcomes.

ALchemy
has already led to improved patient careSoon after the ALchemy study began, it became clear that patients were
benefiting from the more intensive monitoring with the extra appointment after the
first 3 cycles of chemotherapy, monthly blood samples and treatment forms from
the local doctors. As a
result, we have incorporated all of these into our standard clinical practice
for all patients.

Tourmaline AL 1

The trialThis is an international randomised phase 3 trial of a new drug -
MLN9708, in patients with AL amyloidosis with relapsed or refractory disease. MLN9708 belongs to the drug class called
proteasome inhibitors. This drug class also
includes bortezomib, a drug which is often effective treatment for AL
amyloidosis. Patients with relapsed disease have responded to a chemotherapy
treatment regime in the past, but after a while the AL amyloidosis has worsened
again despite continued treatment. Refractory disease means that patients have not responded to the
treatment regime they received. This trial aims to find out if patients with relapsed and refractory AL
amyloidosis respond better to treatment with MLN9708 plus dexamethasone than to
other chemotherapy regimes.

What the
trial involves for patientsIn order to compare the effects of MLN9708 plus dexamethasone to the
effects of other chemotherapy regimes that doctors usually select for patients
with relapsed or refractory AL amyloidosis, each patient taking part in the
trial is randomly assigned to one of the following two groups:

Experimental (MLN9708 plus dexamethasone). Patients will receive MLN9708 (4.0 mg) orally
(PO) on days 1, 8, and 15 plus dexamethasone 20 mg/day PO weekly on days 1, 8,
15, and 22 of each 28-day cycle; dexamethasone may be increased up to 40 mg/day
after 4 weeks, if tolerated.

Active comparator (doctor's choice). Patients will receive one of the following regimes as selected by their doctor:

Who can
take part in the trialPatients with systemic AL amyloidosis affecting the heart and/or kidneys
who have received one or two previous lines of treatment are eligible for
participation in this trial.

OutcomesThe following outcomes will be assessed in this trial:

Overall
response rate (ORR) – this will include estimation of what proportion of
patients have complete response (CR), a very good partial response (VGPR) or a
partial response (PR) to treatment. Response is assessed with the blood test which measures the free light
chain (FLC) concentration. The better
the response to treatment, the greater the drop in FLC concentration.

Hospitalisation rates for heart failure or progression to end state kidney disease or death after 2 years.

In addition, the overall survival (OS), progression free survival (PFS),
the safety and the number of patients with heart and/or kidney response will be
assessed.

TimingThis
study is open for recruitment at the NAC, Oxford, Birmingham and Manchester.

EMN 03

The trialThis is an international randomised multi-centre phase 3
trial comparing oral melphalan-dexamethasone with
bortezomib-melphalan-dexamethasone for patients with newly diagnosed early
stage (stage 1 and 2) AL amyloidosis.

Brief
background on advanced stage AL amyloidosisAdvanced stage cardiac AL amyloidosis is also called stage 2 or stage 3
amyloidosis. Disease stage is determined
according to the results of two specific blood tests called cardiac biomarkers:

brain-type natriuretic peptide (BNP), and

cardiac troponin T (TnT).

The concentrations of these two biomarkers are low at the time of
diagnosis in patients with early stage disease. High concentrations of these two biomarkers at the time of diagnosis are
associated with significant amyloid deposits affecting the heart, and more
advanced disease. In stage 1 cardiac AL amyloidosis, the concentrations of both biomarkers
are low. In stage 2 cardiac AL amyloidosis, the concentrations of one of the
biomarkers is increased, but not the other. In stage 3 cardiac AL amyloidosis, the concentrations of both of the
biomarkers are increased. Recently, an additional measure has also been used to help determine the
disease stage:

What the
trial involves for patientsIn order to assess the effects of the two different chemotherapy regimes
in patients with early stage cardiac AL amyloidosis, each patient taking part
in the trial is randomly assigned to one of the following two treatment regimes:

MDex: Administration of oral melphalan (M) at 0.22
mg/kg and dexamethasone (Dex) at 40 mg daily for 4 consecutive days every 28
days (MDex) until end of therapy.

BMDex: Cycles 1 and 2 = MDex with bortezomib (B) at
1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle, cycles 3 to 8 = MDex
with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.

Who can
take part in the trialUntreated patients diagnosed with stage 1 or 2 cardiac AL
amyloidosis who are not candidates for stem cell transplantation are eligible
for participation in this trial.

OutcomesThe primary outcome assessed will be the number of patients with complete response (CR) and partial response (PR) to treatment. Other outcomes assessed (secondary outcomes) will include:

Complete haematologic response rate after 3 cycles and after completion of therapy.

Haematologic response rate at completion of therapy.

Organ response rates at 3, 6, 9 and 12 months.

Treatment-related mortality.

Toxicity.

Overall and progression-free survival.

Time to haematologic and organ response.

Quality of life.

TimingThis study is open for recruitment.

A study of
genotype and phenotype in plasma cells in patients with AL amyloidosis

The studyThis study will assess the characteristics of abnormal bone marrow
plasma cells in patients with AL amyloidosis.

BackgroundTreatment of AL amyloidosis is chemotherapy targeting abnormal bone
marrow plasma cells. The characteristics
of these cells determines the treatment outcomes. This study seeks to characterise in detail the
abnormal plasma cells by flow cytometry, DNA analysis and exome sequencing.

What the
trial involves for patientsAll patients with AL amyloidosis need a bone marrow test as a part of
the diagnostic work up for amyloidosis and for response assessment at the end
of treatment. This study seeks an
additional bone marrow sample as well as the usual diagnostic sample.

Who can
take part in the trialPatients with systemic AL amyloidosis may participate in this trial,
starting either at the time of diagnosis or after completion of treatment.

OutcomesIt is hoped that the detailed analysis of genetic and other
characteristics of abnormal plasma cells in patients with AL amyloidosis will improve
understanding of development of disease and response to treatment.

TimingThis
study is open for recruitment at the NAC.

The vital amyloidosis study

The trialThis is an international randomised phase 3 efficacy and safety trial of
a new drug – NEOD001, in patients with newly diagnosed AL amyloidosis. NEOD001 is a monoclonal antibody developed
for the treatment of AL amyloidosis. NEOD001
was granted orphan drug designation by the European Medicines Agency in 2013
and by the FDA in 2012.

What the
trial involves for patientsIn order to compare the effects of NEOD001 to the effects
of placebo, each patient taking part in the trial is randomly assigned to one
of the following two groups:

Placebo: Patients will receive intravenous infusion of normal saline once every 28 days.

All patients will also receive standard chemotherapy as
selected by their doctor. First line chemotherapy must be a proteasome
inhibitor containing regimen, with the proteasome inhibitor administered
weekly. Subsequent chemotherapy regimens
may be prescribed at the doctor’s discretion.

Who can
take part in the trialPatients with newly diagnosed, treatment naïve, systemic AL amyloidosis affecting
the heart, for whom the planned first line chemotherapy regimen contains a
proteasome inhibiting agent administered weekly. Patients
with multiple myeloma and patients in whom autologous stem cell transplantation
is planned are not eligible to take part in this trial.

OutcomesThe primary outcome assessed in this trial will be overall survival and hospitalisations because of heart disease.Other outcomes assessed (secondary outcomes) from baseline to 9 months
will include:

NT-proBNP best response.

Change in 6 minute walk test.

Change in scores on standardised questionnaires assessing general health and cardiomyopathy.

Renal and hepatic functions.

TimingThis study is open for recruitment at the NAC.

Trials for ATTR amyloidosis

Brief background on ATTR amyloidosis

Amyloidosis is a disorder of protein folding, where normally soluble
proteins misfold and form abnormal, insoluble amyloid fibrils, which deposit in
the tissues and accumulate to damage the structure and function of tissues and
organs. Transthyretin (TTR) is a normal blood protein which transports thyroid
hormones and retinol (vitamin A), hence its name ‘trans-thy-retin’. All TTR in the blood is produced in the liver;
TTR is also produced in the brain and eye but does not reach the blood from
there.

In ATTR amyloidosis, the amyloid deposits in the organs contain amyloid
fibrils formed from misfolded TTR protein. Normal TTR can form amyloid fibrils in elderly people and there are many
genetically variant types of TTR, which form amyloid much more aggressively and
at an earlier age. There are three
distinct different types of ATTR amyloidosis:

Familial amyloid polyneuropathy (FAP): hereditary - runs in families.

Inherited amyloid cardiomyopathy: hereditary - runs in families.

Senile systemic amyloidosis: not hereditary - does not run in families.

Familial amyloid polyneuropathy (FAP) is by far the most
common form of hereditary amyloidosis. This
disease affects the nervous system, often also the heart and sometimes the
kidneys, eyes and other organs. Disease
symptoms usually appear between the third and seventh decade, although they may
start as early as age 20 or as late as age 80. It is very rare, and the commonest type,
associated with the Val30Met mutation, is thought to affect about 10,000 people
in the whole world. In the UK, FAP is
most common in people of Irish ancestry, carrying the so-called Thr60Ala
mutation. FAP is inherited by autosomal
dominant inheritance, meaning that each child of a person with FAP has a 50%
chance of inheriting the abnormal gene. Liver transplantation was introduced as ‘surgical
gene therapy’ for FAP in 1991, in a collaboration between Swedish colleagues
and our team. Replacement of the
patient’s own liver, producing the amyloidogenic variant of TTR, with a normal
liver producing only normal TTR was intended to halt amyloid formation. More than 2000 patients with FAP, most of
whom carry the Val30Met mutation, have undergone liver transplantation, and it
can lead to prolonged survival, especially in patients who receive their
transplant early in the course of disease. However, since normal TTR is also itself amyloidogenic, the disease
often progresses in many liver transplant recipients.

Inherited amyloid cardiomyopathy (heart disease), presenting
in young adults is an extremely rare hereditary condition in which genetically
variant TTR amyloid principally or exclusively affects the heart. However amyloid cardiomyopathy in elderly black
people, most commonly men over age 60, of West African ancestry, is caused by a
particular TTR variant (Val122Ile) which is present in a significant proportion
of individuals of this genetic background. Because the genetic variant is so common, it
is known as a polymorphism rather than a mutation. Other organs are not affected and there is
very rarely a family history due to the late age of onset and the fact that not
all carriers of the affected gene actually get the disease. This condition has only been recognised in recent
years, was previously rarely diagnosed and is probably much more common than
formerly realised.

Non-hereditary ATTR amyloidosis - 'wild-type' ATTR amyloid deposits

Normal, 'wild-type' TTR may also be amyloidogenic, causing senile systemic amyloidosis: Microscopic deposits of ‘wild-type’ ATTR amyloid are very
common in the elderly, and have been found in 1 in 4 autopsies of people aged
over 80. Until recently it was thought
that these ‘wild type’ ATTR amyloid deposits hardly ever caused disease. However, new imaging techniques have shown that
in fact, disease caused by ‘wild type’ ATTR deposits may be far commoner than
anyone thought. This disease is called
senile systemic amyloidosis, or senile cardiac amyloidosis. Amyloid deposits consisting of ‘wild type’ TTR
mainly affect the heart but may also cause carpal tunnel syndrome in some
people. Senile systemic amyloidosis is
not hereditary (it does not run in families). Most patients with this condition are men aged
over 70 but it can also present before age 60.

Drugs for ATTR amyloidosis

There are no available drug therapies for ATTR
amyloidosis in the UK. However, several
drugs are in varying stages of development and licensing. See below for details of ongoing studies and
studies about to begin at the NAC.

The TRANSCEND study

The full name of this study is: TRansthyretin
Amyloidosis: Neuropathy,
Senility, Cardiomyopathy,
Evaluation, Natural
history and Diagnosis. The goal of TRANSCEND is to achieve a ‘real world’ picture of ATTR
amyloidosis in the UK by close monitoring of all patients with ATTR amyloidosis
regardless of age or disease severity.

ATTR amyloidosis is caused by amyloid deposits made up of a protein
called transthyretin (TTR). There are three distinct different types of ATTR
amyloidosis:

Familial amyloid polyneuropathy (FAP): hereditary - runs in families.

Inherited amyloid cardiomyopathy: hereditary - runs in families.

Senile systemic amyloidosis: not hereditary - does not run in families.

The TRANSCEND study will include patients seen at the NAC with all three
types of ATTR amyloidosis.

ATTR amyloidosis: filling in the gaps in our knowledgeFAPThe FAP World Transplant Registry (FAP WTR) was established in 1995, in
order to compile data on survival of patients who undergo liver transplantation
for FAP and to determine the optimal time for liver transplantation. Most patients who have undergone liver
transplantation carry the Val30Met mutation. However, there is a lack of data on the natural history of non Val30Met
associated FAP, as most of these patients have not undergone liver
transplantation and have not previously been consistently followed in large
numbers. Liver transplantation for FAP does not prevent continued build-up of
ATTR amyloid in the heart. Sometimes the
‘wild type’ TTR produced by the transplanted normal liver may deposit ‘on top
of’ the ‘variant’ ATTR template already present in the heart. There is a need for careful cardiac follow up
of patients who have undergone liver transplantation for FAP, to enhance our understanding
of this process.

Senile
systemic amyloidosis and amyloid cardiomyopathyNewly available cardiac imaging techniques (cardiac magnetic resonance
imaging and DPD scintigraphy) have resulted in greatly increased
diagnosis of
cardiac TTR amyloidosis. There has been
a 40 fold increase in the number of referrals of patients to the NAC
with
senile ATTR amyloidosis over the past decade. ATTR amyloidosis may be a
common cause of heart failure in the elderly. There is a need to
follow these patients systematically
in order to learn about the natural history of this emerging condition,
and to
increase awareness.

Quality of
life (QOL)At present there are no standard, accepted measures of QOL for ATTR
amyloidosis. TRANSCEND aims to establish
and validate such measures, by following QOL throughout the disease course. QOL measures will be useful for assessing the
effects of new drugs for ATTR amyloidosis.

New
treatmentsThere are a number of drugs for ATTR amyloidosis currently in various
stages of development. In order to
arrange future clinical trials of these drugs, and to assess their effects,
there is an urgent need for increased understanding of the natural course of
both cardiac and nervous disease.

What the study involves for patientsPatients will undergo all the standard assessments that are usually
performed at the NAC. The only
difference is that we will record all data in a special database for analysis. These
include:

On-going assessments including posting a monthly Clinical
Progress Form to the NAC, detailing any changes in the medical condition,
patient’s weight or treatment. If there
are marked changes then a member of the NAC study team will conduct a telephone
consultation with the patient.

Six monthly review at the NAC including weight, blood
tests, echocardiography and functional tests such as 6 minute walking distance
and performance status assessment.

Who can take part in the studyAll patients diagnosed with ATTR amyloidosis assessed at the NAC are eligible for the
study if they are capable of providing written, informed consent.

Study aimsThe TRANSCEND study aims to do for ATTR amyloidosis what the ALchemy
study has done for AL amyloidosis. The ALchemy study, which has been running since 2009, follows all
patients diagnosed with systemic AL amyloidosis at the NAC. The data gathered has contributed greatly to
our knowledge and understanding of the full spectrum of this disease in the UK.
Some of our standard clinical management
protocols have been adjusted in the light of the information gathered in this
study. The TRANSCEND study aims to achieve similar goals for ATTR amyloidosis
by following all patients diagnosed with this condition at the NAC. It is a prospective study, which means that
patients will be followed from the time of diagnosis. It is also observational, meaning that the
goal is data collection.

As discussed above, there have not previously been large scale studies following patients with all types of ATTR amyloidosis. Our understanding of the condition is rapidly
evolving, with a significant recent increase in the frequency with which senile
cardiac ATTR amyloidosis is diagnosed. The
only way we can fill in the gaps in our knowledge of this condition is by
carefully following large numbers of patients over time.

The study itself will not involve any alterations in standard clinical
practice. However, it is possible that
understanding gained from this study may eventually influence clinical
management of patients.

TimingThe TRANSCEND study is due to open in 2015 at the NAC but many of the assessments are already being routinely carried out.

Efficacy and safety of ISIS-TTR Rx in familial amyloid polyneuropathy

ISIS TTR Rx is one of a class of drugs called antisense oligonucleotides
which act by a type of gene therapy known as ‘gene silencing’. The drug is not intended to repair the faulty
TTR gene, rather to ‘silence’ its effects by interfering with TTR production in
the liver cells. All proteins in the body are produced in cells by a process called ‘gene
expression,’ using the information present in the genetic code. This process can be likened to the building of
a house. The DNA making up the genes in
the nucleus of each cell are like the architect’s blueprints. Other molecules in the nucleus of the cell,
known as messenger RNA (mRNA) and transfer RNA (tRNA) act like the various
builders, electricians, plumbers, etc, who need to read and follow the
blueprints and communicate effectively together to ensure that the end product
is a success. In the
early steps of protein production, the information contained in the DNA in the
cell’s nucleus is conveyed out of the nucleus by messenger RNA. The messenger RNA contains the instructions
for protein structure which are then translated from the language of genetic
code into the language of amino acids, the building blocks of proteins.

The ISIS TTR Rx molecule is made up of a short string of nucleotides
(the building blocks of the genetic code in DNA and RNA) designed to bind
tightly to TTR messenger RNA. When this
binding occurs, the TTR messenger RNA is broken down by an enzyme in the cell,
preventing the translation step in protein building and thus blocking the production
of both ‘variant’ TTR and normal ‘wild type’ TTR protein. It is hoped that decreasing the amount of TTR protein in the blood will
reduce the formation of ATTR amyloid deposits, slowing or halting disease
progression. After liver
transplantation, wild type TTR from the new liver may continue to deposit as
amyloid fibrils. However, because ISIS
TTR Rx is hoped to reduce the production of both variant and wild type TTR, if
successful, this approach may be more effective than liver transplantation in
halting amyloid deposit progression.

The trialThe purpose of the trial is to determine whether ISIS TTR
Rx can slow or stop the nerve damage caused by ATTR deposits in patients with
FAP. This study will enrol FAP patients
with early stage neuropathy. Patients will
receive either ISIS TTR Rx or placebo for 65 weeks. This is a randomised controlled double blind
phase 3 trial. Phase 1 trials in small
numbers of people have already established that the drug is safe in humans,
have determined an appropriate dosage range, and identified side effects. Phase 3 trials involve a large number of
patients. The trial is multicentre
meaning that patients all around the world are taking part in this trial.

What the trial involves for patientsIn order to see whether ISIS TTR Rx helps patients with FAP, each
patient taking part in the trial will be randomly assigned to one of 2 groups:

Intervention
group - these patients will
receive 300 mg of the ISIS TTR Rx drug by subcutaneous injection 3 times
on alternate days in the first week, then once weekly for 64 weeks.

Control group - these patients will
receive placebo (dummy injection) by subcutaneous injection 3 times on
alternate days in the first week, then once weekly for 64 weeks.

This is a double blind trial. This
means that the doctors and nurses running the trial at the NAC, and the
patients participating will not know which patients are receiving ISIS TTR Rx
and which are receiving placebo.

Who can
take part in the trialPatients with stage 1 and stage 2 FAP, aged between 18 to 75 years who
can walk unaided or with no more than one stick/cane are eligible to take part.

Patients who have undergone liver transplantation or have other serious
diseases are not eligible to take part. For a full list of exclusion criteria,
see the www.clinicaltrials.gov website.

OutcomesThis trial is only designed to assess the effects of ISIS TTR Rx on
neuropathy caused by FAP, not on heart disease.

The main (primary) outcome measures will be change in baseline score in
two standardised measures for assessing the severity of neuropathy:

The modified Neuropathy Impairment Score.

The Norfolk Quality of Life Diabetic Neuropathy questionnaire (this was developed
for patients with diabetic neuropathy and is applicable to FAP even though FAP
has got nothing at all to do with diabetes).

All patients will undergo neuropathy assessment at the start of the
trial, so that there will be a baseline score for comparison. Measurement of the change from baseline in the TTR levels in the blood
will be a secondary measure.

TimingThe trial started recruiting participants in other centres at the end of
2012. Recruitment at the NAC is ongoing.

ALN-TTRSC in ATTR cardiac amyloidosis

ALN-TTRSC belongs to a class of drugs called small interfering RNA
(siRNA) drugs which act by a type of gene therapy known as ‘gene silencing’. The drug is not intended to repair the faulty
TTR gene, rather to ‘silence’ its effects by interfering with TTR production in
the liver cells. All proteins in the body are produced in cells by a process called ‘gene
expression,’ using the information present in the genetic code. This process can be likened to the building of
a house. The DNA making up the genes in
the nucleus of each cell are like the architect’s blueprints. Other molecules in the nucleus of the cell,
known as messenger RNA (mRNA) and transfer RNA (tRNA) act like the various
builders, electricians, plumbers etc who need to read and follow the blueprints
and communicate effectively together to ensure that the end product is a
success. In the
early steps of protein production, the information contained in the DNA in the
cell’s nucleus is conveyed out of the nucleus by messenger RNA. The messenger RNA contains the instructions
for protein structure which are then translated from the language of genetic
code into the language of amino acids, the building blocks of proteins.

The ALN-TTRSC molecule is made up of a short string of nucleotides (the
building blocks of the genetic code in DNA and RNA) designed to bind tightly to
TTR messenger RNA. When this binding
occurs, the TTR messenger RNA is broken down by an enzyme in the cell,
preventing the translation step in protein building and thus blocking the
production of both ‘variant’ TTR and normal ‘wild type’ TTR protein. It is hoped that decreasing the amount of TTR protein in the blood will
reduce the formation of ATTR amyloid deposits, slowing or halting disease
progression. After liver
transplantation, wild type TTR from the new liver may continue to deposit as
amyloid fibrils. However, because ALN-TTRSC
is hoped to reduce the production of both variant and wild type TTR, if
successful, this approach may be more effective than liver transplantation in
halting amyloid deposit progression.

The trialThis is a multi-centre, open-label, multi-dose phase 2 trial. Phase 2 trials are performed at a relatively early stage in drug
development, and the trial aims to recruit only 12 patients. The trial is multicentre meaning that patients and researchers from
different sites (in the UK and the US) are taking part. The
trial is open-label, meaning that all patients and researchers know the drug
and the dose being give. It is not
placebo controlled, meaning that none of the participants will receive a dummy
(placebo) injection.

What the trial involves for patientsEach patient taking part in the trial will receive 10 subcutaneous
injections of ALN-TTRSC on an outpatient basis. In the first week there will be 5 daily doses
on days 0, 1, 2, 3 and 4. After that
there will be 5 weekly doses. There
will be clinic visits for screening up to 28 days before drug administration,
and more visits for follow up up to 90 days after starting participation in the
trial.

Who can
take part in the trialPatients with biopsy proven TTR cardiac amyloidosis, aged between 18 to 80
years who are clinically stable are eligible to take part. For a full list of exclusion criteria, see the www.clinicaltrials.gov website.

ObjectivesThe purpose of the trial is to evaluate the safety and tolerability of
multiple doses of ALN-TTRSC in patients with TTR cardiac amyloidosis. The trial does not aim to assess the effects of ALN-TTRSC on the
patients’ clinical condition. If this
trial finds that ALN-TTRSC is safe and well tolerated, then future, larger
phase 3 trials may evaluate the clinical efficacy of this drug.

TimingRecruitment at the NAC started in December 2013 and is ongoing.

Trial for AA amyloidosis

The trialThis is an international randomised multi-centre phase 3 trial looking at whether a novel
agent, eprodisate, improves outcome in patients with moderate renal disease and
proteinuria.

Brief background on AA amyloidosisAA amyloidosis may complicate chronic infections or
inflammatory diseases. It is characterised
by extracellular deposits of amyloid fibrils composed of fragments of serum
amyloid A protein (SAA), an acute phase reactant protein. The kidney is the most frequent organ
involved, with protein leaking into the urine and renal impairment. Reducing the level of circulating SAA by
treating the underlying inflammatory condition is the current treatment but
this is not always possible. Eprodisate competes
with molecules that encourage early amyloid fibril formation and an earlier clinical
trial suggested that it may slow down progressive renal failure in patients
with AA amyloidosis. This study is
designed to see if that can be confirmed in a larger group of patients.

What the trial involves for patientsIn order to assess the effects of eprodisate in patients with AA amyloidosis, each patient taking part in the trial is randomly assigned to either:

Eprodisate: tablets taken twice daily

Placebo: tablets taken twice daily

Who can take part in the trialPatients with confirmed AA amyloidosis with at least 1 g of proteinuria
and without severe kidney damage (creatinine clearance greater than 20 ml/min).

OutcomesThe primary outcome assessed will be:

the number
of patients whose kidney function gets worse by more than 40% or who reach end
stage kidney failure

Other outcomes assessed (secondary outcomes) will include:

change in
renal function and urinary protein leak over time

overall survival

side
effects and safety

TimingThis study has been recruiting since 2011.

Amyloidosis and Acute Phase Proteins is part of the Division of Medicine